The present invention relates generally to photodynamic therapy, and, more particularly to photodynamic therapy using an irradiation source derived from a phased array Raman laser amplifier.
Photodynamic therapy ("PDT") is an emerging modality in which a photosensitizing drug localizes to diseased tissue upon introduction into the body and it then is activated by light of a specific wavelength. The photosensitizers have biolocalization properties and are optically excitable. That is, upon introduction, there is a period of time during which the photosensitizer is absorbed by all cells, but thereafter, the agent rapidly leaves most normal cells while remaining in any tumerous cells in organs and diseased tissues for a longer period of time. The treated cancer cells are then exposed to light from a laser chosen for its ability to activate the photosensitizing agent. Typically, laser light is focused into a beam so it can be aimed at a specific area of the body being treated, and the laser light normally produces a narrow range of light frequencies. It is known in the PDT field that light in the 600-1000 nm spectral region (the "phototherapeutic window") possesses maximum penetration power into most human tissues owing to the low absorptivity of the normal cell constituents in this region and the relatively inefficient scattering of red light by cell organelles. Therefore, red light, in particular, possesses a high penetration power into human tissues and can be selectively absorbed by red-light-absorbing photosensitizing agents (e.g., certain known porphyrins, chlorins, carbocyanines, phthalocyanines, naphthalocyanines, and derivatives thereof) localized in predetermined sites of the organism.
In any event, photosensitizer agents are used in PDT that capture the light energy at the specific wavelength generated by the laser to create an excited state molecule that causes localized tissue destruction in the presence of oxygen without causing damage to the surrounding healthy tissues. Namely, after absorbing the light of the appropriate wavelength, the photosensitizer becomes activated to a higher energy state capable of generating singlet oxygen molecules that react with cellular components to induce cell death, i.e., they have cytotoxic effects. The light exposure must be timed carefully so that it occurs when most of the photosensitizing agent has left healthy cells but is still present in cancerous ones.
There is a great deal of interest in developing PDT in the oncology field because it does not cause the severe side effects of chemotherapy and radiation therapy, such as nausea, diarrhea, hair loss, and organ failure, and it is less invasive than surgical excision in the case of skin surface cancers. Also, PDT can be used in conjunction with, and not to the exclusion of, conventional cancer treatments, such as with cancer drugs or radiation.
For instance, the standard therapy for skin tumors has been surgical excision. However, photodynamic therapy based on the phototoxicity of photosensitizing agents, such as porphyrins which are the natural precursors of hemoglobin, recently have been effectively used for treatment of skin tumors. Topical application of porphyrins followed by tumor exposure to red light (e.g., in the 630-670 nm .lambda. range) has been shown to be an effective therapy for several types of tumors, such as for solar keratoses, superficial basal cell carcinomas of the skin and Bowen's disease. Also, the U.S. Food and Drug Administration has approved a photosensitizing agent called dihematoporphyrin ether/ester (DHE), or Photofrin-R.TM., to relieve symptoms of esophageal cancer that is causing obstruction and for esophageal cancer that cannot be satisfactorily treated with lasers alone.
However, a problem in the PDT field is that no one type of photosensitizer agent can be universally employed for all conceivable PDT treatments due to the physicochemical, photochemical and photophysical peculiarities of any given photosensitizer agent. Also, some currently used photosensitizer agents for PDT are unstable in vivo or induce hyper-photosensitivity in the patient in the case of certain hematoporphyrins and their derivatives used in treatment of skin tumors. This is spurring continuing research into development of a new generation of PDT photosensitizer agents that avoid these drawbacks. Also, the field is interested in developing photosensitizers that can be effectively used in PDT treatments where needed to deeply penetrate tissues to reach the malignant cells, among other things. As a consequence, new types of photosensitizer agents for PDT are being rapidly researched and developed on an ongoing basis.
These different types of photosensitizer agents can and often do require irradiation at vastly different wavelengths relative to one another for achieving excitation. Also, a laser is needed that operates at an appropriate power level to accommodate factors such as penetration depth of the beam into living tissue. To meet this challenge, practioners in the PDT field have previously resorted to case-by-case searches for laser equipment having wavelength and power attributes that match the requirements of the particular photosensitizer agent desired to be tested or used for a given PDT procedure. This can be a time-consuming process even if an acceptable laser-photosensitizer agent match is ultimately made. Moreover, given that each different type of laser equipment represents a relatively expensive piece of hardware, it also can be costly to proceed in this manner where a wide array of photosensitizer agents are expected to be employed.
Consequently, from the above, it can be appreciated that the scope and potential of PDT could be substantially improved if more versatile laser systems could provided that could accommodate the optical requirements of a wide diversity of photosensitizer agents. The operation of a single efficient laser source for PDT treatments in general at different selectable arbitrary wavelengths for the treatment and photosensitive materials at hand would be of enormous advantage. It is Applicants' recognition that what is needed in this regard is a narrow line width, single frequency-selectable solid state laser amplifier that is both compact and efficient.
Furthermore, to understand the backdrop of laser technology to the present invention, some discussion is thought appropriate on the state of Raman shifted solid state laser technology. One laser transmitter in this regard which has high power output characteristics is a Master Oscillator--Phased Power Amplifier Array (MO)-(PPAA) laser system previously disclosed in commonly-assigned, U.S. application Ser. No. 08/782,175, which was filed on Jan. 14, 1997, now U.S. Pat. No. 5,847,816, and which patent is incorporated herein by reference for all purposes.
As illustrated in FIG. 1, the MO-PPAA laser system includes a MO 100 coupled to a fiber optic power amplifier 200. MO 100 is a stable, very narrow line width, laser, which is operating in a TEM.sub.00 mode at a frequency within the gain spectrum of the power amplifier 200 and which can be coupled by optical fiber to deliver a continuous wave signal to downstream components (not shown).
It will be appreciated that the master oscillator laser 100 can be any conventional master oscillator laser, although the master oscillator is likely a fiber laser oscillator. Some additional conventional components are understood to be part of any practical MO-PPAA laser system and have been omitted. For example, one of ordinary skill in this particular art would appreciate that an optical isolator would be located immediately downstream of the master oscillator 100 to prevent feedback from downstream components, e.g., power amplifier 200, that would induce instability in the master oscillator 100. The details of such components are well known to those skilled in the art and will not be discussed further.
Although a single fiber power amplifier 200 will suffice for some short range applications, a coherent array of optical fiber amplifiers collectively forming the fiber optic power amplifier 200 can be particularly advantageous for those specific applications requiring high output power. One such arrangement of a coherent phased array of fiber optic amplifiers generating high power laser beam is shown in FIG. 1, for example, as needed in long range radar system applications. This particular laser power amplifier is also described in detail in copending, commonly assigned U.S. patent application Ser. No. 08/471,870 and U.S. Pat. No. 5,694,408, which application and patent are also incorporated herein by reference for all purposes.
It will be appreciated that the power splitter, amplifier and phase modulator elements 210 in FIG. 1 may be arranged in various configurations other than the exemplary arrangement illustrated in that Figure. The illustrated fiber optic power amplifier 200 of FIG. 1 includes a first stage composed of a first beam splitter element 210, for splitting a received laser beam into a number N of secondary laser beams. Each of the secondary laser beams is provided to a second beam splitter element 210, which produces a number M of tertiary laser beams from a respective one of the secondary laser beams. Each of the tertiary laser beams is amplified by a respective fiber power amplifier generally denoted 220. It should be mentioned that although two separate stages of beam splitter elements 210 and one amplifier stage 220 are depicted in FIG. 1, the fiber optic power amplifier 200 can have more or less amplification stages. For example, when the first and second beam splitter elements 210 include an optical amplifier 16 pumped by a pump source 18, a beam splitter 24 and, optionally, a number N.times.M of phase modulators, respectively, a total of three amplification devices are included in the power amplifier 220. See FIG. 2a.
Moreover, alternative configurations are possible. For example, the number of series connected elements 210 can be any number greater than or equal to 2. Moreover, element 210 is not limited to the arrangement illustrated in FIG. 2a. For example, the first stage element 210 need not include either an amplifier 16 or a phase modulator 27 (FIG. 2b); alternatively, the first stage element 210 may include optical amplifier 16 but omit phase modulator 27. Needless to say, additional amplifier stages can also be provided.
It will be noted that the fiber optic power amplifier 200 includes a phase modulator 27 in each optical path. These phase modulators 27 are provided to ensure that all of the N.times.M laser beams output by power amplifier 200 arrive at the output of the power amplifier 200 with a predetermined phase profile to minimize transmission losses. The power amplifier 200 thus includes a waveform sensor 230 in the output optical path. The waveform sensor 230 produces sensor signals which are provided to phase modulators 27 in element 210 via an adaptive waveform controller 240. Examples of the construction and operation of waveform sensor 230 and waveform controller 240 are provided in above-referenced copending, commonly assigned U.S. patent application Ser. No. 08/471,870, and U.S. Pat. No. 5,694,408.
Thus, in the system depicted in FIG. 1, the master oscillator 100 generates a signal at a low power level that is coupled into an optical fiber. The signal, which must be within the gain band of the rare earth dopant used in the system, is amplified and split among many fiber optic power amplifiers in power amplifier 200. Each stage of the power amplifier 200 amplifies the signal to a high level and delivers it to a summing aperture with appropriate beam forming optics (not shown). The phase of the signal from each beam line is individually controlled to form a diffraction limited beam from the array. The master oscillator 100 defines the wavelength and waveform of the signal amplified and radiated by the MO-PPAA laser system, subject to the wavelength constraints mentioned previously.
Nonlinear optical processes such as Stimulated Brillouin Scattering (SBS) and Stimulated Raman Scattering (SRS) can rob power from a coherently amplified lightwave produced in power amplifier 200. SBS is a narrowband process whereby forward-going light is scattered into a backward-going wave shifted by 11 Ghz, more or less. SRS, however, is a broad band effect whereby energy from the original wave is downshifted by 53 nm, nominally, into another forward-going wave. Both of these processes have a threshold-like behavior whereby, for a given fiber length, above a certain power level, significant energy is extracted from the coherently amplified wave into the scattered wave at a different wavelength. Below this threshold, the nonlinear process is not a problem.
Spectral data of light emitted from an exemplary fiber 40 meters in length is shown in FIG. 3. The maximum coupled Nd:YAG power sent down the fiber was 130 Watts at the peak, which is slightly above the Raman threshold. The spectral line of the unshifted 1.064 mm light is narrowest. The first-order Raman line is downshifted by 53 nm to 1.117 mm, as expected from silica-glass fibers. The Raman light can itself be Raman shifted another 53 nm into a second-order Raman line, which is clearly shown in FIG. 3. It will be appreciated that a weak emission at 1178 nm is also illustrated in FIG. 3.
FIG. 4 illustrates how much light is emitted from this same exemplary fiber at the fundamental and Raman wavelengths as a function of light power coupled into the fiber. The data demonstrate that SRS is a highly nonlinear process. Once the SRS threshold is reached, the fundamental light power is virtually clamped and the excess power is shifted to the Raman wavelength. It will be appreciated that the Raman light is self aperturing; it can only be generated in, not outside, the core.
The SRS threshold for the exemplary 40 meter piece of optical fiber discussed above is approximately 100 Watts. It should be pointed out that the SRS process is highly nonlinear and thus very sensitive to small variations in parameters such as the mode size, fiber length and core dopants. Since the SRS is highly dependent on these parameters, it is feasible to increase the SRS threshold by increasing the mode diameter, and vice versa. Simulations show that small changes can result in significant increases or decreases in the SRS gain.
The SRS effect can best be understood by considering the laser pulse shapes and shapes of pulses transmitted through the fiber. The top trace of FIG. 6 depicts the shape of the pulse coming directly from a Nd:YAG laser without propagating through the fiber. The output pulse is approximately 100 ms long with a peak power of 500 watts with a brief burst of relaxation oscillations on the leading edge, chosen to simulate quasi-CW conditions in the fiber. The bottom three traces in FIG. 6 are the shapes of light pulses emitted from the fiber. The peak input power of 130 Watts is shown in the first trace, and the lower traces illustrate the temporal shapes of the 1.064 mm light, the 1st order Raman line and the 2nd order Raman line. Due to the highly nonlinear SRS process, small amplitude variations in the coupled light lead to large variations in the fundamental and Raman light components emitted from the optical fiber.
The fundamental-wavelength pulse with its flat top demonstrates the sharp threshold behavior described previously with respect to FIG. 5. Once the threshold is exceeded, additional coupled power is diverted from the fundamental wavelength into the Raman line. Adding the fundamental and 1st order Raman pulses together (note the waveform amplitude scaling) would result in a waveform similar to that of the original laser pulse in the top trace, consistent with the idea that most of the pulse energy is concentrated at the fundamental and 1st Raman wavelengths. The 2nd order Raman line at the 130 Watt peak power level is very small and flickers on and off from pulse to pulse. Its energy is insignificant compared to that at the other two wavelengths at this incident power level.
It should be pointed out that the SRS gain observed is for a high power signal propagating the entire length of the optical fiber. This is not the case for a high power optical amplifier where a 1.06 mm signal is normally injected at a low level and it will gain power over the entire length of the optical amplifier. This gain of the 1.06 mm signal will effectively decrease the total Raman gain available because of the significantly decreased interaction length. Consequently, achieving 100 Watts CW from an optical amplifier will not be limited by SRS.
As discussed above, the nominal Raman shift is about 53 nm. In other instances, the gain coefficient for the Stimulated Raman Scattering in silica fibers peaks at approximately 40 nm from the original signal, as shown in FIG. 6. It will be appreciated that the Raman gain spectrum actually mirrors the LO phonon spectrum in the fiber core, which depends upon the composition of the glass used to form the core. It will also be appreciated that the first-order Raman line depicted in FIG. 3 is considerably broader than the fundamental line at 1.064 mm because of the broad Raman gain spectrum of silica glass shown in FIG. 6.
SRS occurs all along the optical fiber and it is characterized by a differential scattering cross section, which section is integrated over the solid angle of the numerical aperture of the fiber to determine the probability of a spontaneous Raman photon being captured by the fiber and creating the SRS wave. When SRS is present in the fiber or the potential for SRS is present, the power in the signal wave must be increased rapidly so that energy conversion occurs over as short of a fiber length as physically possible. As the high power propagates along the fiber, the Stokes wave begins to grow. If the desired signal power can be reached before the Stokes wave reaches threshold, then the high power fiber amplifier will operate efficiently. It will be appreciated that the Stokes wave threshold is the point at which the gain in the Stokes wave exceeds the distributed losses in the fiber. Consequently, by designing the fiber amplifier to have a distributed loss at the Stokes wavelength, it is possible to completely suppress the generation of the Stokes wave over relatively long fiber lengths.
To see the effect of the build-up of Raman parasitics see FIGS. 7 and 8. In FIG. 7, a properly designed fiber amplifier pumped from both ends can amplify an input signal to the 100 watt level. In FIG. 8, a longer fiber, again pumped from both ends, allows the onset of parasitic Raman amplification gain, which depletes the signal power and converts it to the down-shifted Raman wavelength.
The master oscillator 100 signal is efficiently amplified by the array 200 of high power fiber optic amplifiers illustrated in FIG. 1 if no parasitic SRS occurs in the high power stages. This is assured by design of these amplifier stages. First, since the Raman gain is a function of the signal amplitude, the diameter of the fiber core can be increased within limits to reduce the intensity at a given signal power level. The limitation here is that the fiber should remain essentially single mode. Second, since the onset of the parasitic Raman signal is rather abrupt and depends on the level of down shifted Raman signal present, a Raman filter can be inserted between the tandem stages of each power amplifier line to impede the build up of the Raman signal. Thus in a prior art system, the Raman signal is a detrimental complication that must be controlled by design.
It will be appreciated that the MO-PPAA illustrated in FIG. 1 consists of a phased array of high power fiber optic amplifiers that amplify a signal within the gain band of the rare earth dopant used in the fiber amplifier core. This restricts the useful band of wavelengths to a few tens of nanometers for each of the limited number of rare earth dopants. Even though the output of such an array can be frequency doubled efficiently, the wavelength restriction mentioned immediately above applies equally to the possible harmonic wavelengths. Therefore, for PDT implementations, the FIG. 1 arrangement would be inadequate. More preferably, the postulated laser amplifier would have an output wavelength which is selectable over a range of hundreds of nanometers above the gain band of the rare earth dopant used in the fiber amplifier core of the laser device.
Based on the above and foregoing, it can be appreciated that there presently exists a need in the practice of the photodynamic therapy art for a laser system which overcomes the above-described deficiencies. The present invention was motivated by a desire to overcome the drawbacks and shortcomings of the presently available technology, and thereby fulfill this need in the art.